Inflammatory bowel disease (IBD) comprises two conditions, ulcerative colitis (UC) and Crohn's disease (CD). Both UC and CD are chronic inflammatory diseases of the digestive tract, the former restricted to the large intestine and the latter affecting any part of the bowel from mouth to anus. The cause of both diseases is unknown, but increasing evidence points to a major pathogenic role for reactive oxygen metabolites.
The incidence of UC is about 5/100,000/year; that of CD is similar but rising. The prevalence of each disease is about 60/100,000. The diseases first present most commonly in the third decade, with a second peak of incidence at about 60-80 years. Both diseases occur world-wide, but may be more common in developed countries than in the Third World.
The symptoms of each disease are characterized by periods of relapse and remission over many years. The principal symptoms of UC are diarrhea and rectal bleeding. These symptoms may occur in CD of the colon, but when other areas of the bowel are involved, CD tends to cause abdominal pain, weight loss, malaise, fever, and malabsorption as well as diarrhea. In CD more commonly than UC, strictures, fistulas and abscesses within the abdominal cavity may occur. In up to 10 percent of patients with either disease, there may be arthritis, iritis (eye inflammation), skin disorders (erythema nodosum, pyoderma gangrenosum) and liver disease (chronic hepatitis, cirrhosis, sclerosing cholangitis, cancer of the bile duct, amyloid). In chronic UC affecting the whole colon there is an increased risk of colonic cancer.
Medical treatment of UC and CD is similar and at present unsatisfactory. Active relapses are usually treated with corticosteroids (intravenous, orally or topically) with their attendant side-effects. Sulphasalazine and its derivatives (5-aminosalicylic acid) can be used in active disease and are effective in reducing the incidence of relapse in UC; all have occasionally troublesome side effects. Immunosuppressive agents such as azathioprine and 6-mercaptopurine are used in patients not responding to steroids or sulphasalazine and again have adverse effects. When currently available medical therapy fails, surgical resection of affected bowel is necessary, but this is not curative in CD as disease frequently recurs in residual intestine.
The pathogenesis of IBD is presently being studied. There is now increasing evidence that reactive oxygen metabolites (ROM) are important in the pathogenesis of IBD. See Simmonds et al., Chemiluminescent Assay of Mucosal Reactive Oxygen Metabolites in Inflammatory Bowel Disease, Gastroenterology, 103 No. 1, to appear in July, 1992. The term ROM is used here to include, particularly, free radicals including superoxide, hydrogen peroxide, hydroxyl and hypochlorite. There is now evidence that ROMs may initiate the inflammatory cascade which leads to IBD. Schreck, Reactive Oxygen Intermediates, as Apparently Widely Used Messengers in the Activation of the NF-KB transcription factor and HIV-1, EMBO Journal 10, 2247-58 (1991).
Evidence has been found which demonstrates increased mucosal production of ROMs related to IBD activity, using colorectal biopsies and stimulated mucosal phagocytes. Keshavarzian et al., Excessive Production of Reactive Oxygen Metabolites by Inflamed Colon: Analysis by Chemiluminscence Probe. Gastroenterology, 1992, (in press); Williams, Phagocytes, Toxic Oxygen Metabolites and IBD: Implications for Treatment, Ann. R. Coll. Surg. Engl., 72, 253-62 (1990); Simmonds et al., cited above. Further, it has been shown that enough ROMs are produced to cause mucosal damage. Increased lipid peroxides have been found in rectal biopsies of patients with active UC, and 8-oxo-7-hydrodeoxyguanosine, produced by hydroxyl attack on DNA, has been found in the ileocolonic mucosa of patients with CD, as well as in the circulating lymphocytes of patients with UC. Ahnfelt-Ronne et al., Clinical Evidence Supporting the Radical Scavenger Mechanism of 5-aminosalicylic Acid, Gastroenterology 98, 1162-69 (1990); Simmonds et al., Reactive Oxygen Metabolites Damage DNA in IBD, abstract submitted to the British Society of Gastroenterology for presentation in September, 1992.
Thus, there is strong evidence that ROMs are instrumental in the pathogenesis of both ulcerative colitis and Crohn's disease, and that the severity of the disease is related to the extent of their over-production. Antioxidant therapy or agents preventing or blocking the formation of ROMs can therefore prove beneficial.
In experimental colitis in animals, specific agents blocking the release or effect of ROMs have been shown to decrease inflammation. E.g., Fretland et al., Superoxide Dismutase Modulates Acetic Acid-Induced Colitis in Rodents. Gastroenterology 100, A581 (1991). Studies in man showed promise for the use of allopurinol in pouchitis. Levin et al., Role of Oxygen Free Radicals in the Etiology of Pouchitis, Dis. Colon Rectum 35, 452-56 (1992). Superoxide dismutase injections showed promise in refractory CD. Emerit et al., Phase II Trial of CuZnSOD in CD. Free Radic. Biol. Med. 7, 145-49 (1989). Furthermore, sulphasalazine and its derivatives may work in IBD, at least in part, by scavenging ROMs. Yamada et al., Antioxidant Properties of 5-Aminosalicylic Acid: Potential Mechanism for its Antiinflammatory Activity. In Williams, Ed., Trends in IBD Therapy, Lancaster: Klumer Acad. Publ., 73-84 (1990); Ahnfelt-Ronne et al., cited above.
There is currently much interest in the relationship between oxidant stress and the development of cancer. Weitzman et al., Inflammation and Cancer: Role of Phagocyte-Generated Oxidants in Carcinogenesis, Blood 76, 655-63 (1990). While there is no doubt that ROM can cause oxidative DNA damage leading to base changes, strand breaks, and enhanced expression of proto-oncogenes, and that oxidative stress can induce malignant transformation in cell culture [Halliwell et al., DNA Damage by Oxygen-Derived Species, FEBS Letters 281, 9-19 (1991)], the relationship between these observations and the development of malignancy in vivo is more complex and will depend on other factors such as rate of damage, antioxidant defenses, DNA repair mechanisms and the necessity for multiple steps (initiation, promotion and progression). It has been shown that constitutive and oxidant-induced levels of adenosine diphosphate ribosyl transferase (ADPRT), an enzyme involved in DNA repair, are reduced in patients with IBD and also those with colon cancer. Markowitz et al., Hydrogen Peroxide Induced ADPRT Response in Patients with IBD, Gut 29, 1680-86 (1988). It is therefore reasonable that long-term antioxidant therapy in IBD could reduce not only inflammation but also the incidence of colorectal cancer. Pero et al., Oxidative Stress, DNA Repair and Cancer Susceptibility, Cancer Detec. Prev. 14, 555-61 (1990).
There is a clear need for a new potent and safe treatment for the suppression as well as prevention of relapse of IBD. Such treatment might not only improve the bowel disorders themselves, thereby reducing the need for ablative surgery, but also reduce the incidence of the joint, eye, skin and liver complications of IBD.